The invention relates to methods for treating a metabolic disorder (e.g., obesity or diabetes) by increasing invariant NKT cell activity.
Obesity and the resulting metabolic syndromes, including type 2 diabetes, are serious threats to current and future global health. Obesity-related metabolic diseases are critically linked to inflammation. Adipose tissue is now thought of as an endocrine organ central to energy homeostasis and a specialized immune organ with a unique lymphoid repertoire. Adipose inflammation activates local immune cells, leading to inappropriate responses and insulin resistance. Thus, adipose immunity is now recognized as a major player in regulation and development of metabolic disorder.
Macrophage infiltration, activation and phenotypic changes can lead to insulin resistance. T cells, including ‘natural killer T’ cells (‘NKT’) can activate macrophages. T cell IFNγ enhances pro-inflammatory macrophage phenotype, while T cell anti-inflammatory cytokines such as IL-4, IL-13 and IL-10 enhance anti-inflammatory macrophages. Recently, four studies described several immune cell types in murine adipose, including inflammatory mast cells and cytotoxic T cells and complementary protective T regulatory cells, and their positive or negative impacts on metabolic syndrome.
Invariant NKT cells (iNKT) are a unique population of T cells with highly conserved T cell antigen receptors (TCR) that represent an important bridge between innate and adaptive immunity. iNKT appear to function in infectious and immune-mediated diseases and cancer. iNKT recognize lipid antigens presented by CD1d on e.g., tumor cells. They respond rapidly to these lipid antigens by killing the tumor cells and releasing cytokines that activate and regulate adaptive immune responses. Synthetic glycolipids, e.g., alpha-galactosylceramide (αGC), can also be used to bind CD1d and activate iNKT. Thus, iNKT are targets in early clinical trials for cancer and infectious diseases.
Correlations of depleted iNKT levels with other pathologies and disease conditions also have been proposed, e.g., liver disease in obese mice (Li et al., Hepatology. 42:880-5, 2005; and Elinav et al., J Pathol. 208:74-81, 2006), and studies with Beta 2 microglobulin (b2m) KO mice have shown, e.g., macrophage infiltration and glucose intolerance (Ohmura et al., Arterioscler Thromb Vasc Biol. 30:193-9, 2010; Geiben-Lynn et al., J Biol Chem. 284:33800-6, 2009; and Koh et al., J Immunol. 181:4560-9, 2008). Loss of a provoking CD8 T cell population, however, may compensate for loss of protective effects of iNKT (e.g., Nishimura et al., Nat Med. 15:914-20, 2009).
Accordingly, methods by which iNKT activity is modulated may be useful in the treatment of disease conditions.